The long term objective of this research is to produce an effective vaccine to protect humans from HIV-1 infection. HIV-1 presents several challenges to vaccine design: (1) high mutation rates result in tremendous diversity of virus envelope, the target of neutralizing antibody, such that antibody elicited to one envelope may not protect from virus with a distinct envelope; (2) envelope directly from infected persons differ from envelopes obtained from T-cell line cultures, the usual source of envelope for vaccines; (3) envelope glycoprotein exists as oligomers on the virion surface, not as monomers in previous vaccines. To address these challenges we proposed to deliver diverse, oligomeric, patient-derived envelopes to induce multiple type-specific responses capable of recognizing native envelope on natural variants. To recruit these array of long-lived B and T cells we propose a 3- tiered sequential vaccine strategy: () DNA vaccine priming-> (2) live vector vaccination->(3) purified protein boosting. These 3 alternate moieties are selected to trigger helper T cells, cytotoxic T cells and B cells, each considered important correlates of protection. Studies proposed here focus first on Phase I trials on a multi-envelope recombinant vaccinia virus vaccine (PolyEnv1) which is central to this approach (aims 1-3) followed by introduction of DNA priming and protein boosting (aim 4). Specific aims are: Aim 1. Determine the safety of PolyEnv1, a novel multi-envelope recombinant vaccinia virus vaccine. Aim 2. Characterize the envelope-specific humoral response induced in the Phase I study of PolyEnv1. Aim 3: Characterize the envelope-specific cellular immune responses elicited in the Phase I study of PolyEnv1. Aim 4. Determine the safety and immunogenicity of a multi-envelope DNA vaccine and a recombinant gp140 protein vaccine.